1. Field of the Invention
This invention relates to a novel compound, glycookadaic acid and its salt, its preparation and its use, in particular, treating or preventing cachexia and a side effect caused by TNF.
2. Description of Related Art
Cachexia is a state of serious symptoms caused by cancer and infective disease such as fervescence, chills, trepidation, weight reduction, inappetence, hypotension, decrease in plasma protein, general lassitude, decrease in fat and the like.
Treatment of cachexia relies only on transfusion therapy to recover the whole body state, at present, and there are neither good methods of treatment nor any specific medicines therefor. Thus there have been demanded medicines for treating and preventing cachexia.
Old et al. found that when endotoxin is injected in mice immunized with BCG (Bacille de Calmette et Guerin), a substance causing hemorrhagic necrosis in tumor nodules induced by subcutaneous implantation of tumor cells increases in serum.
This substance was isolated and named "tumor necrosis factor" (TNF). TNF is a physiologically active substance produced by macrophages, and it was thought that TNF shows cytotoxic effect on malignancy cells, but does not adversely affect normal cells (Carswell, E.A. et al., Proc. Natl. Acad. Sci. USA, Vol. 72, pp. 3666-3670 (1975)). The TNF has been recently called TNF.alpha. (Wong, G.H.W. et al., Nature, 323, 819-822 (1986)).
On the other hand, it is recently reported that cachectin which has been studied as a factor elevating plasma lipid in the case of infective diseases is substantially the same substance as TNF (Beutler, B. et al., J. Exp. Med., 161, 984-995 (1985)).
Further, it is suggested that cachectin is possibly a cause of a part of syndromes of endotoxin shock upon infection of gram-negative bacteria (Beutler, B, et al., Nature, 316, 552-554 (1985)).
In addition, in a Phase I clinical study of recombinant human-tumor necrosis factor (rHu-TNF) there were observed adverse reactions such as mostly fever, chills, trepidation, and, at a lesser rate, hypotension, elevation of GOT/GPT, general fatigue, elevation of ALP, pain in the extremities, decrease in platelets, and the like, and further, in some cases elevation of neutral lipid in plasma was also observed (Taguchi, T., Jpn. J. Cancer Chemother., 13, 3491-3497 (1986)).
In view of the foregoing the cachexia-like side effects of IF are an important problem in the course of developing TNF as an anticancer drug.
The present inventors have conducted wide screening of compounds for preventing or treating cachexia and for decreasing or preventing side effects of TNF and found that glycookadaic acid of the formula [I](infra) isolated from Halichondria okadai Kadota is effective for preventing or treating cachexia and further for decreasing or preventing side effects of TNF.